Neurofibromatosis 2 is a dominantly inherited disorder characterized by the occurrence of multiple nervous system tumors, particularly schwannomas and meningiomas. Both the familiar tumors of NF2 and equivalent sporadic tumors in the general population, are caused by inactivation of a tumor suppressor gene encoded in chromosome band 22q12. In the past grant period, we successfully isolated the NF2 gene and discovered the identity of this novel tumor suppressor. We named the new protein merlin, because of its striking similarity to moesin, ezrin and radixin, members of the protein 4.1 family thought to link cytoskeletal components with proteins in the cell membrane. Merlin thus represents a new class of tumor suppressor whose function may be mediated by interactions with the cytoskeletal network. Now that the search for the NF2 gene has been completed successfully, the next step in comprehending the disorder fully is to establish the normal function of merlin, and how loss of the protein disrupts growth control. The similarity between merlin and these other three proteins suggests that it too may associate with both membrane and cytoskeletal structures. However, the distinct localization and behavior of moesin, ezrin and radixin, indicate that merlin probably performs a different role from each of these other proteins. When this function is disrupted, growth regulation can be disrupted and tumor formation results. Indeed, each isoform of merlin might have a distinct role. Thus, it is our intention to define the forms and patterns of expression of merlin, its intracellular localization in normal and tumor cells, its behavior in response to various cellular stimuli, and the identity of the proteins with which it normally associates. These investigations will provide the baseline of information concerning merlin that is now available for other members of the protein 4.1 family, and will provide the basis for specific hypotheses concerning merlin's role as a tumor suppressor. In the long- term, this line of investigation may form the foundation on which to develop effective treatments to prevent the formation or to slow the growth of the tumors associated with NF2 and their sporadic counterparts.